1. Field of the Invention
The present invention relates to novel methods for the treatment of central nervous system dopamine-deficiency diseases (CNS-DADD's). The present invention further relates to improved methods of using levodopa in the treatment of a CNS-DADD. Also the present invention provides novel pharmaceutical compositions of levodopa and 3',4'-dihydroxy-2-methylpropiophenone (DHMPP).
The CNS-DADD's include classical Parkinson's disease (paralysis agitans) as well as other parkinsonisms. Such other parkinsonisms include, for example, post-encephalitic parkinsonism and symptomatic parkinsonism. The latter condition may, for example, occur following injury to the nervous system by chemical intoxication (e.g., with carbon monoxide and manganese).
Classical Parkinson's disease or paralysis agitans is characteristically a progressive disease which becomes manifest primarily in the elderly and is marked by a mask-like physiognomy, a characteristic tremor of the resting muscles, a slowing of voluntary movements, a festinating (or accelerating) gait, peculiar posture, and muscular weakness. Parkinson's disease is occasioned by a neuroregulator (dopamine) deficiency or depletion in the central nervous system in the sense that increasing CNS dopamine levels provides symptomatic relief to a patient. In Parkinson's disease, as well as other CNS-DADD's, administration of dopamine itself does not provide symptomatic relief, since the dopamine apparently does not cross the blood-brain barrier.
However, a metabolic precursor of dopamine, levodopa or 3-(3,4-dihydroxyphenyl)-L-alanine, does cross the blood-brain barrier and has long been recognized as effective in the alleviation of CNS-dopamine deficiency, thus providing symptomatic relief of the disease.
Biochemically, the transformation of levodopa to dopamine is accomplished enzymatically by dopa decarboxylase, i.e.: ##STR1##
Since dopa decarboxylase is present both within the central nervous system and outside of it (e.g., the peripheral nervous system), levodopa administered to a patient is rapidly converted to dopamine in extracerebral tissues. This requires that large doses of levodopa be administered in order to assure that effective doses of levodopa do indeed cross the blood-brain barrier. Accordingly, peripheral dopa decarboxylase inhibitors, i.e., extracerebral inhibitors of dopa decarboxylase, have been employed concomitantly with levodopa. Since such inhibitors act only in extracerebral tissues (i.e., do not cross the blood-brain barrier), they permit dopamine production in the central nervous system while preventing excessive and undesirable dopamine production outside the central nervous system. The use of the peripheral dopa decarboxylase inhibitor, by permitting much lower doses of levodopa, is beneficial in that a reduction in the adverse effects of levodopa administration (e.g., nausea and vomiting) is experienced.
3',4'-Dihydroxy-2-methyl-propiophenone (DHMPP) is known in the art to be useful in relieving dysmenorreha, forestalling spontaneous abortion, and other conditions in which relaxation of uterine smooth muscle is indicated. Further, this compound is otherwise generally known as a muscle relaxant. See, for example, U.S. Pat. No. 2,929,484, describing its preparation and uses.
DHMPP is a compound of the following structural formula: ##STR2## This compound, like levodopa and dopamine, is structurally a catechol in that it contains a vicinally dihydroxylated benzene group, i.e., ##STR3##
DHMPP is known to exhibit numerous other pharmacological effects. Some of these effects are reported in the following scientific references:
Moffett, R. B., et al., "Central Nervous System Depressants. V. Polyhydroxy and Methoxyphenyl Ketones, Carbinols, and Derivatives", J. Med. Chem. 7:178-186 (1964);
Miller, J. W., et al., "Potentiation of the Inotropic Actions of Certain Catecholamines by U-0521 (3,4-dihydroxy-alpha-methyl propiophenone) on the Isolated Atria of the Rabbit", Pharmacologist 8:203 (1966);
Giles, R. E., et al., "The Catechol-O-methyl Transferase Activity and Endogenous Catecholamine Content of Various Tissues in the Rat and the Effect of Administration of U-0521 (3,4-dihydroxy-2-methyl propiophenone)", J. Pharmacol. Exp. Ther. 158:189-194 (1967);
Trendelenburg, U., et al., "Influence of Block of Catechol-O-methyl Transferase on the Sensitivity of Isolated Organs to Catechol Amines", Naunyn-Schmiedeberg's Arch. Pharmacol. 271:59-92 (1971);
Bausher, L. P., et al., "Potentiation of the Effects of Topical Epinephrine on the Pupil and Intraocular Pressure in the Sympathetically Denervated Rabbit Eye by a Catechol-O-Methyl-transferase Inhibitor", Invest. Ophthalmol. 15:854-857 (1976);
Gillespie, J. S., et al., "Influence of Iproniazid and 3,4-Dihydroxy-2-Methylpropiophenone U-0521 on Uptake and Metabolism of Norepinephrine by Rabbit Colon", Naunyn-Schmiedeberg's Arch. Pharmacol. 293(Suppl):R3 (1976); and
Kaumann, A. J., "Activation of Myocardial .beta.-Adrenoreceptors by the Nitrogen-free Low Affinity Ligand 3',4'-Dihydroxy-alpha-methylpropiophenone (U-0521)", Naunyn-Schmiedeberg's Arch. Pharmacol. 296-228 (1977).
Among the pharmacological properties of DHMPP described above is the inhibition of the enzyme catechol-O-methyl transferase (COMT). COMT is effective in converting levodopa to 3-O-methyldopa, as indicated in Diagram II. ##STR4##
Absent the inhibition of COMT, levodopa is converted in part to 3-O-methyldopa (OMD) and the corresponding 3-O-methyldopamine (OMDA). To the extent that levodopa is converted to OMD and OMDA in vivo, it is not available for decarboxylation to dopamine, the active principle in the treatment of CNS-DADD's.
2. Prior Art
As indicated above, DHMPP is known in the art, as are numerous pharmacological actions of DHMPP, including its activity in the inhibition of COMT. See Giles, R. E., et al., J. Pharmacol. Exp. Ther., 158:189-194 (1967).
Also known in the art is the treatment of CNS-DADD's with levodopa and combinations of levodopa and a dopa decarboxylase inhibitor. See, for example, the description of the actions and indications of combinations of levodopa and carbidopa in Physicians' Desk Reference, 31st Ed., published by Medical Economics Company, 1977, page 1101.
Further the treatment of Parkinson's disease with combinations of levodopa and a COMT inhibitor is reported in the art. See Ericsson, A. D., J. Neurol. Sci. 14:193 (1971), reporting the use of N-butyl gallate. Further, for a review of other COMT inhibitors, including a discussion of their toxicity, see Angel, A., et al., Nature 217:84 (1968) and Guldberg, H. C., et al., Pharm. Rev. 27:135 (1975).
Finally, for a discussion of the relative levels of levodopa and OMD in CNS-DADD patients, see Muenter, N. D., et al., Mayo Clin. Proc., 47:389 (1972), Fahn, S., Neurology 24:431 (1974), and Sharpless, N. S., et al., Clin. Chim. Acta. 31:155 (1971). The correlation of high plasma levels of OMD with dopa-induced impairment of voluntary movements (dyskinesias) is reported in Rivera-Calimlin, L., et al., Arch. Neurol. 34:228 (1977) and Fuerstein, C., et al., Acta. Neurol. Scandinav. 56:79 (1977).